FDA Panel Votes Against DMD Therapy Deramiocel

Deramiocel (Capricor Therapeutics), an investigational cell therapy for treating cardiomyopathy in patients with Duchenne muscular dystrophy (DMD), was dealt a major blow on Wednesday after an FDA advisory committee voted against the evidence supporting its efficacy. In a 9-3 vote, with no abstentions, the FDA's Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) concluded that the available evidence does not support the efficacy of deramiocel for treating DMD-associated cardiomyopathy.Capricor submitted a biologics license application (BLA) for deramiocel in June 2025, relying primarily on cardiac and functional data from the phase 2 HOPE-2 trial. The FDA issued a complete response letter on July 11, citing insufficient evidence of effectiveness and chemistry, manufacturing, and controls concerns. Capricor resubmitted the BLA with additional data from the phase 3 HOPE-3 trial, but the committee concluded that unresolved questions surrounding the trial's statistical analysis prevented the data from establishing deramiocel's cardiac benefit. As part of Capricor's presentation to the advisory committee, Craig McDonald, MD, principal investigator of the HOPE-2 and HOPE-3 trials, said, "HOPE-3 met the primary endpoint.""The prespecified primary analysis gives a mean difference of 4.55% in favor of deramiocel, with a P value of.029, which corresponds to a 1.2-point absolute change in total PUL [Performance of the Upper Limb] 2.0," he added. A 1-point or greater increase in the PUL 2.0 score is generally considered clinically meaningful, McDonald added, noting that a prespecified sensitivity analysis of the absolute change in PUL 2.0 resulted in a P value of.05.Prateek Shukla, MD, an acting branch chief in the FDA's Center for Biologics Evaluation and Research, disagreed. "The results are unambiguous. The primary endpoint, mean change from baseline in PUL 2.0 total score at month 12, showed a mean difference of 0.66 points favoring deramiocel with a P value of 0.24. This is not a near miss. The study did not meet its primary endpoint," Shulka said.Several committee members who voted no said that discrepancies between the FDA's and Capricor's analyses of HOPE-3, together with inconclusive secondary cardiac findings, did not provide sufficient evidence of a clinically meaningful benefit.The HOPE Program Deramiocel is an investigational allogeneic cell therapy made of cardiosphere-derived cells intended to reduce inflammation and fibrosis associated with DMD. Improvements in respiratory care have extended survival in patients with DMD. Cardiomyopathy has become the leading cause of DMD mortality, yet no therapies are currently approved specifically for DMD-associated cardiomyopathy.The HOPE clinical development program began with the phase 1/2 HOPE-Duchenne trial, which supported the feasibility and safety of intracoronary cell delivery. It advanced to the phase 2 HOPE-2 trial, which evaluated repeated intravenous (IV) infusions and showed improvements in upper limb function along with exploratory cardiac signals. HOPE-2 and its open-label extension formed the basis of Capricor's original BLA, which the FDA found insufficient for the cardiomyopathy indication.Capricor then conducted the phase 3 HOPE-3 trial to confirm earlier findings and evaluate effects on both skeletal muscle and cardiac outcomes.Data presented at the 2026 American Academy of Neurology Annual Meeting reportedly showed statistically significant results for the primary functional endpoint and a key cardiac endpoint. However, FDA reviewers raised concerns about the statistical methods used and whether the cardiac data constituted substantial evidence of effectiveness.The SAP Debate Committee members discussed whether HOPE-3 data were sufficient to support the approval for the cardiomyopathy indication, noting that the trial's primary endpoint was a measure of skeletal muscle (upper limb) function, not a cardiac outcome.During Capricor's presentation, Linda Marbán, PhD, co-founder and CEO of Capricor Therapeutics, criticized the FDA for relying on the statistical analysis plan (SAP) version 1.1, calling it an unfinished draft that was never finalized for analysis of the trial data. She argued this approach underestimated the treatment effect."For reasons we do not understand why, the FDA has seized upon that unfinished, unsigned draft SAP and performed numerous analyses based on this incomplete draft," Marbán said.The HOPE-3 results, analyzed using Capricor's preferred SAP version 3.0, were published online July 29 in The Lancet, the same day as the advisory committee meeting.FDA reviewers used SAP version 1.1, which they considered the prespecified plan, and found no statistically significant treatment effect on the primary endpoint or key secondary cardiac endpoints under that model."The models specified in SAP 1.1 are consistent with those specified in SAP 1.2 through 1.5," Tingting Zhou, PhD, an FDA statistician, said during the FDA's presentation. "Notably, the analytical models and missing data handling are similar across all SAP versions and protocol versions that preceded the interim futility analysis."Capricor argued that SAP version 3.0 was finalized before unblinding and represented the appropriate prespecified analysis; under that version, the company reported a statistically significant reduction in 12-month PUL 2.0 decline with deramiocel.Several committee members questioned the extent of Capricor's revisions to the SAP, while others criticized the FDA for not providing feedback on SAP 2.0 before SAP 3.0 replaced it.Capricor maintained that the totality of evidence from HOPE-2, HOPE-3, and long-term follow-up consistently demonstrated preservation of cardiac and skeletal muscle function."The FDA's conclusions are based on post-hoc analyses and a disregard for pre-specification," Marbán said. "Overall, the benefits of deramiocel far outweigh the potential risk of hypersensitivity, especially in light of the inevitable muscle loss and disease progression that ultimately takes the lives of these young boys and men."Trial Results and the Committee's Votes In HOPE-3, investigators randomly assigned 106 boys and young men, aged 10 years or older, with advanced DMD to repeated IV deramiocel or placebo. The trial met its primary endpoint, showing improvement in the PUL 2.0 score with deramiocel (least-squares mean difference, 4.55%; 95% CI, 0.47-8.63; P = .029).The key secondary cardiac endpoint, change in left ventricular ejection fraction (LVEF), did not reach statistical significance under the FDA's primary analysis (P = .0935), although results numerically favored deramiocel. Other cardiac measures, including fibrosis and LVEF among patients with baseline cardiomyopathy, were considered supportive but secondary."This is a biomarker for cardiomyopathy, and it is prognostic, but has not been shown [to be a surrogate] — and I didn't see evidence of it being a surrogate. A P value of.09 in the context of missing data, without diving in, concerned me. That's why I voted no," said panel member Lori E. Dodd, PhD, a biostatistician at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.Not all votes at the meeting were negative. Patient representative Debra L. Dunn, voted yes, citing the lack of alternatives for families: "They don't have an alternative... I was trained many years ago [that]..: risk over benefit and benefit over risk. That's why I voted yes."Public Comment and Reaction During the open public hearing, patients, caregivers, and advocacy organizations urged the committee to weigh DMD's limited treatment options and the inevitable progression.One mother, Jessica Roth, described her son's experience on deramiocel. "My son's gain in arm function and 5 years of stability would not be possible without deramiocel. Twenty-four-year-olds typically cannot use their [arms] without treatment... there has been no new fibrosis from a cardiac perspective in eight years. That is a really big deal to my family. Please approve deramiocel, so all young men can benefit."Still, several committee members reiterated that regulatory approval requires substantial evidence of efficacy, not sympathy for unmet need alone.Patient advocacy organizations expressed disappointment with the recommendation while encouraging FDA to continue working with developers on therapies targeting Duchenne cardiomyopathy."We believe regulatory decisions should be guided by rigorous science, meaningful clinical data, and patient safety, while also reflecting the seriousness of Duchenne, the urgent unmet medical need, and the totality of the available evidence," said Debra Miller, founder and CEO of CureDuchenne, who attended and spoke at the meeting, in a statement."We also believe the voices and priorities of patients and families should remain central to these important decisions."What's Next Although CTGTAC's recommendation is not binding, the FDA frequently follows advisory committee votes in making approval decisions. The agency is expected to weigh the 9 to 3 vote, its own briefing documents, and the totality of clinical evidence ahead of a final decision on Capricor's BLA. The Prescription Drug User Fee Act target action date is set for August 22, 2026.Disclosure information for study authors is available in the original study publication.